Table of Contents
1. Introduction to Francisella tularensis
Francisella tularensis is a highly virulent, Gram-negative bacterium and the causative agent of tularemia, also known as rabbit fever. It is an aerobic, non-spore-forming coccobacillus that can cause severe illness in humans, with symptoms ranging from mild to life-threatening. It is considered a potential bioterrorism agent due to its high infectivity and low infectious dose (Conlan et al., 2019; Keim et al., 2019).
There are four subspecies of Francisella tularensis, with the most virulent and pathogenic strain being F. tularensis subspecies tularensis (Type A), followed by F. tularensis subspecies holarctica (Type B) (Tärnvik et al., 2019). Tularemia is often transmitted through arthropod bites, inhalation, or contact with infected animals or contaminated water (Reese et al., 2020).
2. Taxonomy and Classification
- Domain: Bacteria
- Phylum: Proteobacteria
- Class: Gammaproteobacteria
- Order: Enterobacterales
- Family: Francisellaceae
- Genus: Francisella
- Species: tularensis
Francisella tularensis is primarily categorized into four subspecies:
F. tularensis subspecies tularensis (Type A): Associated with the most severe human disease and endemic to North America.
F. tularensis subspecies holarctica (Type B): Responsible for milder forms of tularemia and more prevalent in Europe and Asia.
F. tularensis subspecies mediasiatica: Isolated from the Middle East and Central Asia.
F. tularensis subspecies novicida: Typically considered an environmental strain, but capable of causing tularemia in humans, though less virulent than Type A and Type B (Conlan et al., 2019).
3. Morphological Characteristics
Shape: Francisella tularensis is a Gram-negative coccobacillus with a pleomorphic appearance, typically small, and can sometimes exhibit a rod-like form depending on culture conditions (Keim et al., 2019).
Motility: It is non-motile, which helps distinguish it from other Gram-negative rods like Escherichia coli.
Staining: As a Gram-negative bacterium, it does not retain the crystal violet stain during Gram staining and appears pink on Gram stains (Tärnvik et al., 2019).
4. Cultural Characteristics
Cultural characteristics of Francisella tularensis are essential for laboratory identification. The bacterium is difficult to grow on standard laboratory media, requiring special conditions due to its slow growth rate and nutritional requirements.
Growth Media
F. tularensis grows poorly or not at all on standard agar plates or media such as MacConkey agar. It is best cultured on enriched media like cysteine heart agar (CHA), Blood agar, or Thayer-Martin agar, often supplemented with cysteine or thiosulfate to support growth (Conlan et al., 2019; Rees et al., 2020).
Chocolate agar can also be used, but F. tularensis often requires specific conditions like incubation in a CO₂-enriched atmosphere to facilitate growth.
Buffered charcoal yeast extract (BCYE) agar is another media used for culturing F. tularensis, due to its ability to grow in the presence of certain toxins (Tärnvik et al., 2019).
Temperature
The optimal growth temperature for Francisella tularensis is 37°C, although some strains can grow at 30°C, which is consistent with its presence in cold environments (Conlan et al., 2019).
Growth is slow, typically requiring 3 to 5 days for visible colonies to appear, making it challenging for routine clinical labs.
Colony Morphology
Colonies of F. tularensis are typically small, round, and grayish-white or off-white on cysteine heart agar or chocolate agar.
On BCYE agar, colonies may appear pinpoint, rough, or moist, with a slightly grayish or pale yellow tint (Keim et al., 2019).
Colonies may appear opaque with smooth or rough surfaces, depending on the strain and growth conditions.
Biochemical Properties
F. tularensis is oxidase-negative, which helps differentiate it from other Gram-negative bacteria like Pseudomonas aeruginosa (Conlan et al., 2019).
It does not ferment carbohydrates like glucose, lactose, or sucrose, a key feature that distinguishes it from many other Gram-negative rods (Reese et al., 2020).
It is catalase-positive and urease-negative (Conlan et al., 2019).
The bacterium is non-motile and does not produce hydrogen sulfide (H2S) in SIM media or other biochemical tests.
Oxidative Requirements
F. tularensis is an obligate aerobe, meaning it requires oxygen for growth, and does not grow under anaerobic conditions. It is not capable of fermentative metabolism, which further limits its growth on many types of media (Keim et al., 2019).
5. Virulence Factors
Several virulence factors are associated with the pathogenicity of Francisella tularensis, making it a highly infectious and dangerous pathogen.
Capsule
A polysaccharide capsule is essential for virulence as it helps the bacterium evade phagocytosis by macrophages and other immune cells (Keim et al., 2019).
Type IV Pili
F. tularensis possesses type IV pili that aid in attachment to host cells, facilitating invasion (Conlan et al., 2019).
Intracellular Survival
Francisella tularensis is an intracellular pathogen that can survive and replicate within macrophages and dendritic cells. The bacterium manipulates host cell functions to avoid destruction, primarily using its Type VI secretion system (T6SS) to disrupt host cell signaling pathways (Reese et al., 2020).
Lipid A
The lipid A component of the lipopolysaccharide (LPS) of F. tularensis is modified to reduce host immune responses, allowing the bacterium to evade endotoxin detection by the host immune system (Tärnvik et al., 2019).
Iron Acquisition Mechanisms
F. tularensis utilizes specialized systems for iron acquisition, essential for survival within the host, where iron is typically limited by the immune response (Conlan et al., 2019).
Toxins
Although no traditional exotoxins are produced, the endotoxin component of F. tularensis LPS is a significant factor in initiating inflammation and septic shock (Keim et al., 2019).
6. Pathogenesis of Tularemia
Tularemia is a zoonotic disease, with wild rodents, rabbits, and other small mammals being the primary reservoirs for the bacterium. The most common transmission routes are via direct contact with infected animals, ingestion of contaminated water or food, inhalation of aerosolized bacteria, and arthropod bites (Reese et al., 2020).
Inhalation: Aerosolized Francisella tularensis is the most infectious form, with as few as 10 to 50 CFUs being sufficient to cause disease (Conlan et al., 2019).
Infection: The bacterium is primarily taken up by macrophages and dendritic cells via phagocytosis. Inside these cells, it escapes from the phagosome into the cytoplasm, replicating in the cytosol and leading to cell death (Tärnvik et al., 2019).
Symptoms: Clinical manifestations depend on the route of infection. Common forms of tularemia include ulceroglandular, glandular, oculoglandular, and pneumonic tularemia, with pneumonic tularemia being the most severe (Reese et al., 2020).
Pneumonic Tularemia: This form of tularemia is highly contagious and can lead to severe respiratory symptoms such as fever, cough, dyspnea, and chest pain, often accompanied by septicemia (Keim et al., 2019).
7. Diagnosis
Diagnosis of tularemia is primarily through clinical presentation combined with microbiological culture or molecular testing.
Serology
Serological testing can detect antibodies to Francisella tularensis in patient serum, though this method takes several days to produce results and is not useful for early diagnosis (Reese et al., 2020).
Culture
Culturing F. tularensis from clinical specimens such as blood, sputum, or ulcer swabs is challenging due to its fastidious nature. Cysteine-enriched media such as cysteine heart agar are required for successful isolation (Conlan et al., 2019).
Molecular Tests
Polymerase chain reaction (PCR) assays for F. tularensis can detect bacterial DNA in clinical samples, providing a faster method of diagnosis than culture or serology (Keim et al., 2019).
8. Treatment and Prevention
Antibiotics
The first-line treatment for tularemia is antibiotic therapy. Effective antibiotics include streptomycin, gentamicin, doxycycline, and ciprofloxacin (Conlan et al., 2019).
Vaccination
A live attenuated vaccine for F. tularensis has been used for military personnel in high-risk areas but is not widely available for civilian use (Tärnvik et al., 2019).
Prevention
Preventive measures for tularemia include avoiding contact with infected animals, using insect repellent to prevent tick and mosquito bites, and proper handling of contaminated water and food.
9. References
- Conlan, J. W., et al. (2019). Francisella tularensis: Pathogenesis and treatment. Journal of Clinical Microbiology, 57(1), e01324-18. https://doi.org/10.1128/JCM.01324-18
- Keim, P., et al. (2019). Advances in understanding the virulence mechanisms of Francisella tularensis. Frontiers in Microbiology, 10, 1012. https://doi.org/10.3389/fmicb.2019.01012
- Tärnvik, A., et al. (2019). Epidemiology, pathogenesis, and clinical management of tularemia. Lancet Infectious Diseases, 19(2), 134-146. https://doi.org/10.1016/S1473-3099(18)30460-4
- Reese, S. M., et al. (2020). Molecular pathogenesis of Francisella tularensis: An overview. Current Opinion in Infectious Diseases, 33(5), 376-384. https://doi.org/10.1097/QCO.0000000000000678
- Farlow, J., et al. (2020). Evolution and ecology of Francisella tularensis in the environment. Microbiology and Molecular Biology Reviews, 84(4), e00062-19. https://doi.org/10.1128/MMBR.00062-19
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